Amyloid beta-peptide (AB) accumulation and toxicity in the brain are central events in the pathogenesis of Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein (LRP) interacts with beta-amyloid-precursor protein (APP) and regulates its endocytic trafficking and processing to AB. LRP is also a major receptor in the brain for apolipoprotein E (apoE), which modulates AB clearance, cholesterol metabolism, and cellular signaling. Previous studies have detected abundant functional soluble LRP (sLRP) in peripheral and our preliminary work has detected sLRP in human brain and cerebral spinal fluid (CSF). Molecular and cellular studies have defined Notch/APP-like sequential processing of LRP by matrix metalloprotease (MMP) and by b- and g-secretases. Our long-term goal is to understand how LRP proteolysis is regulated in the brain and dysregulated in AD, and how these proteolytic events and processing products impact its function in apoE metabolism and signaling, as well as APP trafficking and processing to AB. Our preliminary studies have shown that a g-secretase cleavage product, APP intracellular domain (AICD), regulates LRP expression and function by directly binding to LRP promoter. Our studies also identified a novel adaptor protein, sorting nexin 17 (SNX17), that modulates endocytic trafficking and processing of both LRP and APP. Our central hypothesis is that LRP and APP proteolytic processing is dysregulated in AD by pathological ligands and trafficking events, and that this in turn impairs LRP expression and function in apoE metabolism and signaling in the brain. We propose four specific aims to test our hypothesis: 1) to identify LRP shedding enzymes and examine the functional impact of altered LRP shedding on apoE metabolism and signaling;2) to examine how LRP expression, shedding, and proteolysis are altered in AD mouse models and during aging and AD in humans;3) to study how APP processing products and other g-secretase cleavage events regulate LRP expression and function;and 4) to analyze how altered endocytic trafficking of LRP and APP by neuronal adaptor proteins influences their proteolytic processing, apoE metabolism and AB production. Together, these studies should allow us to define the mechanism and regulation of LRP expression, processing and function in the brain during aging and AD. Our proposed studies may also identify novel targets for AD diagnosis and therapy. PUBLIC HEALTH RELEVANCE: The major objective of our proposal is to understand how an apoE receptor LRP undergoes proteolytic processing and how these cellular events are regulated in the brain. Because apoE is a major risk factor for Alzheimer's disease, a leading cause of dementia in elderly, our results may provide knowledge for diagnosis and/or therapy for Alzheimer's disease.